evidence-based Pharmacy Practice

An overview of gastropathy induced by

nonsteroidal anti-inflammatory drugs
Natalie Schellack, BCur, BPharm, PhD
Senior Lecturer, Department of Pharmacy, Faculty of Health Sciences, University of Limpopo (Medunsa Campus)
Correspondence to: Natalie Schellack, e-mail: nschellack@gmail.com
Keywords: NSAID, COX, COXIB, gastropathy, NSAID-induced gastrointestinal toxicity

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) constitute a well-known group of drugs that are most widely used for a variety of
inflammatory conditions and pain. However, their gastrointestinal side-effects, i.e. ulcers and gastrointestinal bleeding, hamper their
usefulness in many clinical settings. The selective cyclo-oxygenase 2 (COX-2) inhibitors (the coxibs) promised to be a group of antiinflammatory drugs with significantly fewer, or no gastrointestinal side-effects. Nevertheless, more recent research into their effectiveness
and safety profiles revealed that they are also associated with an increased risk of upper- and lower-gastrointestinal toxicity. Guidelines
suggest that patients at risk of NSAID-induced gastrointestinal ulcers and toxicity should be given preventative treatment. However,
only a small percentage of these patients receive any therapeutic intervention. Multiple strategies exist for reducing the risk of NSAIDinduced gastrointestinal complications. An overview of these strategies and treatment options is provided in the article, as well as
novel approaches to developing gastrointestinal-sparing NSAIDs (using selective inhibition of terminal prostaglandin synthases, and
modified NSAIDs to slowly release gastroprotective gaseous mediators, e.g. nitric oxide and hydrogen sulphide).
Medpharm

S Afr Pharm J 2012;79(4):12-18

Introduction

NSAID-induced gastropathy

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of

drugs that are widely used to alleviate the symptoms associated
with conditions in which an inflammatory component is present,
e.g. osteoarthritis and rheumatoid arthritis, as well as several
instances of somatic pain. In addition to NSAIDs, low-dose aspirin
(acetylsalicylic acid or ASA) is used for the primary and secondary
prophylaxis of both cerebrovascular and cardiovascular events.1-4
It is also well-recognised that NSAIDs have severe gastrointestinal
side-effects, ranging from dyspepsia to gastroduodenal ulcers and
bleeding.3

The following important aspects form the basis of our current

understanding of NSAID-induced gastropathy:1-6
The use of NSAIDs is an important cause of upper-gastrointestinal
adverse events.
NSAIDs-induced gastrointestinal toxicity can also involve the
lower-gastrointestinal tract.
The coxibs, or cyclooxygenase-2 (COX-2) enzyme-selective
NSAIDs, e.g. celecoxib, are also associated with an increased risk
of upper-gastrointestinal adverse outcomes.
Parenteral NSAIDs are also associated with a significantly
increased risk of lower-gastrointestinal toxicity.

These agents are prescribed and used frequently in all age groups,
but especially in the elderly population. Up to 70% of the elderly
take NSAIDs on a weekly basis.3 Only a small proportion of patients
using these agents develop gastrointestinal toxicity. However,
due to the large numbers of patients using them, this still places a
significant burden on the healthcare system.3

According to a recent study,6 when comparing celecoxibs

with non-selective NSAIDs, the risk of developing lowergastrointestinal toxicities appears to be equal.

Pathophysiology of NSAID gastric damage and

other toxicities

Numerous factors may increase the risk of upper gastrointestinal

complications, including ulceration. In a resource-limited country
like South Africa, in which a significant number of patients
are seen at primary healthcare level (including community
pharmacies), it is important to note that additional risk factors
for early identification of gastrointestinal events or toxicity exist.
These risk factors have been included in a suggested checklist for
the pharmacist, and can be used per patient, per visit (see Table I).

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The NSAIDs, including aspirin, cause gastric mucosal damage in

two specific ways (refer to Figure 1), namely:7
Systemic inhibition of endogenous mucosal prostaglandin
synthesis.
Direct or topical irritation of the gastric epithelium.

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Table I: Risk assessment for gastrointestinal events3,5
Risk factors

Visit 1

Visit 2

Visit 3

Visit 4

Visit 5

Visit 6

Comments Comments Comments Comments Comments Comments

Use of multiple NSAIDs (including OTC NSAIDs

and aspirin)
Dosage (higher dosages increase the risk)
Month of NSAID use*
Prior ulcer complications
Advanced age (especially over 65 years)
Rheumatoid arthritis
Concomitant use of corticosteroids, e.g.
prednisone
Concomitant use of selective serotonin-reuptake
inhibitors, e.g. fluoxetine
Concomitant use of anticoagulants, e.g.
warfarin, and antiplatelet agents
* It is interesting to note that the greatest risk of gastrointestinal complications occurring exists during the first few months of treatment,

Rheumatoid arthritis, appears to independently increase the risk of adverse gastrointestinal events,3

Selective serotonin-reuptake inhibitors, when used alone or in combination with NSAIDs, substantially increase the risk of upper gastrointestinal haemorrhage5

Systemic inhibition of endogenous mucosal prostaglandin

synthesis is the result of their inhibition of the COX enzyme. COX
is the rate-limiting enzyme in the conversion of arachidonic acid

Mechanisms of action

to prostaglandins (PGs), and is inhibited by the NSAIDs. Two COXisoforms have been identified, namely COX-1 and COX-2 (refer to
Table II).

Taking an NSAID

Blood flow is reduced

NO production
PMN activation
Formation of oxygen
radicals

iNOS

Detrimental
physiological effects

Cyclo-oxygenase-2
inhibition

Adhesion of white blood cells

Inflammation

Topical irritation

Result
Protection of the
gastrointestinal mucosa
Cyclo-oxygenase-1
inhibition

Epithelial damage

NO = nitric oxide, PMN = polymorphonuclear neutrophils, iNOS = nitric oxide synthase

Adapted from reference 1

Figure 1: Pathogenesis of gastric damage induced by nonsteroidal anti-inflammatory drugs (including aspirin)

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Release of tissue-damaging proteases and oxygen-derived free
radicals, once neutrophils have been activated.

Table II: The regulation and location of the cyclo-oxygenase isoforms7

COX-1

COX-2

Location (where Mostly found in body

they are normally tissue, which includes
found)
the stomach, kidneys,
intestines and platelets.

Undetectable in most
tissues during normal
physiological conditions,
but is particularly
expressed in inflammatory
conditions and arthritis.

Functions

Mostly induced
unregulated through
inflammatory stimuli such
as cytokines, which then
produce prostaglandins
that are responsible for
fever and pain.
Is also expressed under
normal physiological
circumstances in the brain,
kidneys and reproductive
tract.

Produces protective
prostaglandins that
regulate physiological
processes, such as:
Gastrointestinal mucosal
integrity
Platelet homeostasis
Renal function.

The inhibition of COX-2 induces neutrophil adherence when

NSAIDs are administered. Therefore, when a selective COX2 inhibitor is administered, it may spare much of the total PG
synthesis by the mucosa.1 It also triggers the key event in the
pathogenesis of NSAID-induced gastropathy.1
The topical irritant properties associated with NSAIDs are mostly
linked with the more acidic NSAIDs, such as aspirin.7 This is due
to their ability to decrease the hydrophobicity of the mucous gel
layer in the gastric mucosa.7 Aspirin is the most damaging of all
the NSAIDs, although most of them have topical irritant effects.7
Other formulations of the NSAIDs, e.g. prodrugs, parenteral
formulations, rectal preparations, and enteric-coated aspirin,
may be associated with less acute topical gastric mucosal injury,
but may still be involved with varying degrees of gastrointestinal
toxicity, due to their systemic inhibition of endogenous PGs.7
Cardiovascular-related toxicity, due to the administration of COX2 inhibitors, led to the withdrawal of the bestseller in this class,
namely rofecoxib, from the global market. However, cardiovascular
toxicity has now been linked to non-selective NSAIDs as well, with
the possible exclusion of naproxen.1 The cardiovascular toxicity
associated with COX-2 inhibitors may be due to the inhibition of the
synthesis of prostacyclin (PGI2), which may have anti-thrombotic
properties, while sparing thromboxane A2 (TXA2), a prothrombotic
substance.1 PGE2 is the PG that is primarily associated with
inflammation. If this PG could be selectively inhibited, it may
prove to be an option for the reduction of inflammation, without
the associated cardiac risk profile.

The side-effects associated with the NSAIDs are due to the nonselective inhibition of COX-1, while their anti-inflammatory
properties are due to the inhibition of COX-2. Non-selective or
traditional NSAIDs, e.g. NSAIDs such as ibuprofen and diclofenac,
inhibit COX-1 and COX-2, whereas the selective COX-2 inhibitors,
e.g. celecoxib, are highly-selective inhibitors of the COX-2 isozyme.7
So why is COX-2 associated with adverse gastrointestinal
outcomes? The original hypothesis was that selective COX-2
inhibitors would spare COX-1-mediated PGs, and only inhibit the
production of COX-2-mediated PGs involved in the inflammatory
process.1 However, COX-2 is involved in the mucosal defence and
repair, and it seems that both the COX-isoforms are responsible
for the physiological processes of tissue injury. In animal studies,
where COX-1 was selectively inhibited, it did not seem that
the inhibition resulted in significant gastric damage.1 In other
studies, where selective COX-2 inhibitors were compared to
NSAIDs in relation to gastric complications, they produced severe
gastrointestinal complications less frequently than NSAIDs, but
when compared to placebo, clinically significant gastrointestinal
injuries appeared more frequently than in the control group.1

Signs and symptoms associated with

NSAID-induced peptic ulceration
The clinical manifestations of peptic ulceration (PU) may depend
on the severity thereof. With NSAID-induced ulcers, uppergastrointestinal bleeding, perforation, and obstruction, may be
some of the most serious, life-threatening complications. The
bleeding associated with PU may be due to the erosion of the
ulcer into an artery.7 Depending on the site of the bleeding, it may
be occult, or present as black-coloured stools (melena), or the
patient may vomit blood (hematemesis).7

The addition of aspirin to a selective COX-2 regimen further

reduces the benefit of the ulcer-sparing abilities, and increases the
ulcer risks.7 The use of clopidogrel and other medicines that impair
angiogenesis do not cause ulcers, but rather prevent the healing
of gastric erosions that may lead to ulceration and bleeding.7
Angiogenesis is important for the repair of gastrointestinal
mucosal disruptions.2 Furthermore, following the administration
of NSAIDs, leukocytes (mostly neutrophils) tend to adhere to the
vascular endothelium of the gastric microcirculation. This seems
to be a critical event in the formation of gastric ulcers. When this
step was inhibited in laboratory animals, it seemed as though
gastric ulcers were prevented.1

Table III highlights the common signs and symptoms of peptic

ulceration.

Diagnosis of NSAID-induced gastropathy

When attempting to diagnose peptic ulcer disease, specific
tests have to be requested to enable an accurate diagnosis. A
patient presenting with a bleeding ulcer will need to undergo
a haematocrit (Hct) and haemoglobin (Hb) test as part of their
work-up, to determine the extent of the bleeding. When there
is a concern that there may be concomitant infection with
Helicobacter pylori, specific tests will have to be conducted to
include or exclude this diagnosis. Gastric acid secretory studies
may have to be performed.

However, the neutrophil adhesion in the vascular endothelium

contributes to NSAID-induced gastropathy in two ways:
Physical obstruction of capillary flow.

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General

Mild epigastric pain, or it may present with acute, lifethreatening, upper-gastrointestinal complications

be feasible, especially in a patient with a severe debilitating

inflammatory condition, such as arthritis. Figure 2 presents a
possible algorithm for the management of vulnerable patients on
long-term NSAIDs, and those who also have cardiovascular risks.

Signs

Weight-loss with nausea, vomiting and anorexia.

It illustrates the following basic principles:3,4

Table III: Clinical presentation of peptic ulceration or peptic ulcer

disease7

Complications including bleeding ulcer, perforation,

penetration, or obstruction.

When a patient requires long-term NSAID therapy, the need

for the NSAID should be reviewed, and alternative treatment
approaches sought.

Symptoms Abdominal pain.

Nocturnal pain presenting between midnight and 03.00,
waking the patient from sleep.

If no other alternative exists, the NSAID should be used at the

lowest possible effective dosage, for the shortest possible time.

Heartburn, belching and bloating that accompany the pain.

Nausea, vomiting and anorexia, which are usually associated
with a gastric ulcer, rather than a duodenal ulcer.

If the patient is going to be on long-term NSAID-therapy,

a gastrointestinal and cardiovascular risk profile should be
completed using the patients history, physical examination,
and laboratory investigations, as needed.

May be seasonal, and may occur more frequently in the spring

or autumn.
Episodes may present in clusters that may last for weeks, and
then the patient may go into remission for weeks to months, or
even years.

The lowest effective dose of aspirin should be initiated in

patients with an increased cardiovascular risk.

More invasive tests will need to be performed to confirm the

diagnosis, but also to determine the extent of the gastric
involvement.
These could include the following:
Fibre-optic upper endoscopy: This confirms up to 90% of peptic
ulcers, and can allow the treating physician to directly inspect
the lesions, take a biopsy, and visualise superficial erosions, as
well as envisage active bleeding sites.
Radiography, with barium, can also be carried out to detect and
diagnose peptic ulcers. Some authors view this as the procedure
of choice for suspected peptic ulcers.
The diagnosis should be made using the patients clinical picture,
and the clinical laboratory tests, where available.3,4,7

Pharmacotherapeutic strategies for the

prevention and treatment of NSAID-induced
ulcers

Naproxen may be used in patients with a low gastrointestinal

risk and a high cardiovascular risk, because it has the lowest
cardiovascular risk profile in the group.
If a patient needs naproxen and aspirin, the addition of a
gastroprotective agent, such as a PPI, should be considered.
Testing for Helicobacter pylori in patients with a high-risk of
NSAID-related gastrointestinal bleeding should be considered.
A coxib and a PPI may offer good gastrointestinal protection in a
patient with a very high risk of an upper-gastrointestinal event.
When a patient has both a high gastrointestinal and
cardiovascular risk profile, then NSAIDs should be avoided.
If this is not possible, then the physician should prioritise
the cardiovascular and the gastrointestinal risks. If the
gastrointestinal risk is the primary concern, a COX-2 inhibitor
plus a PPI, should be given. If the cardiovascular risk is the
primary concern, then naproxen and a PPI should be considered,
especially if the patient is already on aspirin.

Other treatment options

Misoprostol

Principles of reducing risk

When identifying and reducing the risk of NSAID-induced
gastrointestinal ulcers, the following therapeutic principles may
be used:3,7
Co-therapy with the NSAID and a proton-pump inhibitor (PPI), or
misoprostol, reduces the ulcer risk and associated complications
in high-risk patients.
Using a non-selective COX-2 inhibitor, instead of a non-selective
NSAID, does not completely eliminate ulcers and complications
for at-risk patients, but may reduce the risk, provided that
the patients cardiovascular profile has been taken into
consideration.
When selecting a gastroprotective strategy, the patient
should be evaluated holistically, by taking into account the
cardiovascular risks and concomitant antiplatelet therapy.

Identifying a risk profile for patients

The risk may be reduced by substituting the NSAID with a nonNSAID analgesic, such as paracetamol. This may not necessarily

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Ulcer prophylaxis may be achieved by using misoprostol when

the patient has to remain on NSAID therapy.3,8 Misoprostol
is a synthetic prostaglandin E1-analogue, which replaces the
cytoprotective PGs that are depleted by the NSAIDs from the
gastrointestinal mucosa.3,8 Its efficacy in preventing ulcers in
patients using NSAIDs has been demonstrated in various studies,
where the efficacy has been proven above the use of placebo.3,8
Although the use of misoprostol has been demonstrated to reduce
the risk of gastrointestinal events, it has been proved to have its
own spectrum of side-effects. Side-effects associated with the use
of misoprostol include abdominal pain, nausea, and diarrhoea,
and it should be avoided in women of childbearing potential.3,8
The side-effect profile, and frequent dosing needed with
misoprostol, makes compliance to therapy increasingly difficult.
Comparative studies have shown that the PPIs may be more
effective in patients with NSAID-induced gastric ulcers.3 Headto-head studies comparing PPIs to either low- or high-dose

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Low GI risk

Rx: A suitable t-NSAID

High CV risk
(on ASA)

Rx: Naproxen + PPI

Low CV risk

Rx: Coxib alone

Or t-NSAID + PPI

Low CV risk

The patient who requires

NSAID therapy

Determine whether
both the patients
GI and CV risks are
high or low

High GI risk
High CV risk
(on ASA)

Cannot avoid
NSAID

Very high GI risk

(primary concern):
Rx: Coxib + PPI
Very high CV risk
(primary concern):
Rx: Naproxen + PPI

Avoid NSAID if
possible

ASA = American Society of Anesthesiologists, CV = cardiovascular, GI = gastrointestinal, PPI = proton-pump inhibitor,

Figure 2: Algorithm for the use of NSAIDs in high-risk patients, i.e. those with gastrointestinal and cardiovascular risks8

misoprostol found no significant difference between PPIs and

misoprostol in the prevention of endoscopic ulcers. However, the
PPIs proved to be superior in the prevention of duodenal ulcers.8

receptor antagonists may be effective in reducing NSAID-induced

duodenal ulcers, but not gastric ulcers (the ulcer type most
frequently associated with NSAIDs).7

Fixed-dose combinations of misoprostol and diclofenac

(Arthrotec) have shown a less-frequent association with
endoscopically-diagnosed ulcers.3 The incidence of side-effects
with misoprostol is dose-dependent. However, reducing the dose
will reduce both side-effects and efficacy.3

When given at high doses, the H2-receptor antagonists, e.g.

famotidine 20 or 40 mg twice daily, may reduce the incidence
of gastric and duodenal ulceration.3,7 Having stated that, it
is not recommended that these agents are used routinely in
asymptomatic patients receiving NSAIDs, since this may mask
dyspeptic symptoms associated with mucosal injury.3,7 PPIs have
proven to be superior in healing gastroduodenal ulcers in patients
using NSAIDs, and are better in preventing ulcer recurrence.3,7

Sucralfate
Sucralfate is a basic aluminium salt of sucrose octasulfate, which
forms an adherent complex at duodenal ulcer sites.3,7 It may
be beneficial to use when treating NSAID-induced duodenal
ulcers, provided that the causative NSAID has been stopped.3,7
Sucralfate has not been shown to be effective in the prevention
of NSAID-related gastric ulcers. Its routine use for this purpose is
not recommended, due to the availability of superior therapeutic
options.3,7

PPIs (omeprazole, esomeprazole, lansoprazole, rabeprazole

and pantoprazole)
These agents bind irreversibly to the proton pump (H+-K+-ATPase),
inhibiting basal and stimulated gastric-acid secretion.3,4,7 They
are administered as prodrugs that are activated in the acidic
environment of the parietal cells.3 Lansoprazole has been proven to
protect and heal the gastric mucosa after gastric damage induced
by a NSAID via a novel mechanism of action, which uses antiapoptotic action mediated through regulating factors involved in
mitochondrial and Fas-mediated death pathways of apoptosis.9
In addition to inhibiting acid secretion, lansoprazole also seems
to offer gastroprotection through inhibition of apoptosis, and

H2-receptor antagonists (cimetidine, ranitidine, famotidine and

nizatidine)
These agents act by competitively inhibiting the action of
histamine at the H2-receptor site on the gastric parietal cell, and
thereby modulating the gastric pH.3 Standard dosages of the H2-

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stimulation of cell survival and proliferation.9 After three to four
days of therapy, the degree of acid suppression increases, as more
of the proton pumps are inhibited. They act only on activelysecreting proton pumps, and should be taken 30-60 minutes prior
to having a meal.

Endogenous gaseous mediators, such as nitric oxide (NO) and

hydrogen sulphide (H2S), exhibit many PG-like effects in the
gastrointestinal tract.1 NO is already known for its vasodilatory
mechanism of action. However, it can also inhibit leukocyte
adherence to the vascular endothelium.1,10 Administration of these
agents increases the resistance of the gastric mucosa to injury by
the NSAIDs, or other noxious substances.1,10

The PPIs are available in various dosage forms and formulations,

which include delayed-release, enteric-coated dosages that have
pH-sensitive granules in a gelatine capsule, rapidly disintegrating
capsules, and delayed-release enteric-coated tablets.

This presents an opportunity to couple NO and H2S with the

NSAIDs, and may prevent, or even compensate for, the inhibition
of gastric PG-synthesis. NO and H2S also has anti-inflammatory
properties, thereby boosting the anti-inflammatory properties of
the NSAIDs in question.1,10

Similar healing times are seen in five of the PPIs, omeprazole,

lansoprazole, rabeprazole, pantoprazole and esomeprazole, with
similar maintenance times for ulcer healing and symptom relief,
when used at the recommended dosages.3,7

Conclusion
The use of NSAIDs is an important cause of gastropathy. It was
always thought that only the non-selective NSAIDs were the
causative agents, but the selective COX-2 inhibitors have now also
been shown to be associated with untoward gastrointestinal sideeffects. NSAID-related ulcers require an individualised assessment
of a patients current disease state and medication use. More
importantly, the patient should be assessed for his or her risk of
gastrointestinal and cardiovascular toxicities. If the patient needs
to continue on the NSAID, then an appropriate regimen should
be sought, with the best possible efficacy, and lowest possible
number of side-effects. New advances have been made in
designing novel anti-inflammatory drugs, with reduced toxicity.
Coupling of NSAID-moieties that slowly release gastroprotective
gaseous mediators, such as NO and H2S, appears to be a promising
new approach to reduce the toxicity of these agents.

In conclusion, the PPIs, especially when used as co-therapy to

NSAIDs, reduce the risk of NSAID-induced gastric and duodenal
ulcers, and are better tolerated than misoprostol. All of the PPIs are
equally effective when used at standard dosages, and they reduce
the risk of NSAID-related ulcer bleeding.3,7,9 Chronic use of PPI
therapy may be associated with an increased risk of infection and
nutritional deficiencies, as gastric acid plays a role in the defence
against bacterial colonisation and nutrient absorption.3,7 Patients
should be carefully monitored when using chronic therapy with
the PPIs.3,7,9
COX-2 inhibitors (celecoxib and rofecoxib)
As a result of concerns regarding their cardiovascular safety, and
recent information on their related gastrointestinal toxicity, the
use of coxibs should be evaluated, and the risks vs. the benefits
for each patient carefully weighed up. Celecoxib is no longer
considered to be a selective COX-2 inhibitor, as it carries the same
gastrointestinal warnings as the non-selective NSAIDs.3,7

References
1. Wallace JL, Vong L. NSAID-induced gastrointestinal damage and the design of GI-sparing
NSAIDs. Curr Opin Investig Drugs. 2008;9(11):1151-1156.
2. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert Consensus document
on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the
American College of Cardiology Foundation task force on clinical expert consensus documents. Circulation. 2008;118(18):1894-1909.
3. Scheiman JM, Fendrick AM. Practical approaches to minimizing gastrointestinal and cardiovascular safety concerns with COX-2 inhibitors and NSAIDs. Arthritis Res Ther. 2005;7 Suppl
4:S23-S29.
4. Chan FKL, Abraham NS, Scheiman JM, Laine L. Management of patients on nonsteroidal antiinflammatory drugs: a clinical practice recommendation from the First International Working Party on Gastrointestinal and Cardiovascular Effects of Nonsteroidal Anti-inflammatory
Drugs and Anti-Platelet Agents. Am J Gastroenterol. 2008;103(11):2908-2918.
5. Loke YK, Trived AN, Singh S. Meta-analysis: gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2008;27(1):31-40.
6. Chang CH, Lin JW, Chen HC, et al. Non-steroidal anti-inflammatory drugs and risk of lower
gastrointestinal adverse events: a nationwide study in Taiwan. Gut. 2011;60(10):1372-1378.
Epub 2011.
7. Berardi RR, Fugit RV. Peptic ulcer disease. In: DiPiro JT, Talbert RL, Yee GC, et al (editors). Pharmacotherapy: a pathophysiologic approach. 8th ed. New York: The McGraw-Hill Companies;
2011.
8. Rostom A, Moayyedi P, Hunt R. Canadian consensus guidelines on long-term nonsteroidal
anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks. Aliment Pharmacol and Ther. 2009;29(5):481-496.
9. Maity P, Bindu S, Choubey V, et al. Lansoprazole protects and heals gastric mucosa from nonsteroidal anti-inflammatory drug (NSAID) induced gastropathy by inhibiting mitochondrial
as well as Fas-mediated death pathways with concurrent induction of mucosal cell renewal.
Journal of Biological Chemistry. 2008;283(21):14391-14401.
10. Brzozowski T. Novel physiological and pharmacological avenues in the mechanism of gastrointestinal integrity, protection and ulcer healing. Curr Med Chem. 2012;19(1):2-3.

There seems to be a dosage-dependent correlation with

cardiovascular toxicity for celecoxib.3,7 The increase in the
cardiovascular toxicity appears to relate to the dosage and the
duration of use.3,7 When using these agents, they should be given
at the lowest possible dosage, for the shortest possible duration.3,7
The gastric side-effects of the COX-2 inhibitors appear to be
similar to those of the non-selective NSAIDs, namely dyspepsia,
abdominal pain, fluid retention, hypertension, and renal toxicity.3,7
New approaches: gaseous mediator-releasing NSAIDs
As discussed in the section on pathophysiology, the hypothesis
exists that the deficiency of PGs in the gastrointestinal mucosa can
lead to ulceration. This has opened up new opportunities for drug
development.1 Some of these were developed in the 1980s for
use in the prophylaxis of NSAID-induced gastrointestinal injury.
Unfortunately, some were associated with adverse effects, such
as diarrhoea and abdominal pain.1 Other endogenous mediators
that may produce PG-like effects, such as mucosal defence, have
brought about the development of novel NSAIDs that can slowly
release gastroprotective substances.1,10

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